Cdk5 and GSK3β inhibit fast endophilin-mediated endocytosis

• Published in: Nature communications 2021-04, Vol.12 (1), p.2424-2424, Article 2424
• Main Authors: Ferreira, Antonio P. A., Casamento, Alessandra, Carrillo Roas, Sara, Halff, Els F., Panambalana, James, Subramaniam, Shaan, Schützenhofer, Kira, Chan Wah Hak, Laura, McGourty, Kieran, Thalassinos, Konstantinos, Kittler, Josef T., Martinvalet, Denis, Boucrot, Emmanuel
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/89; 14/19; 631/80/313; 631/80/313/1461; 631/80/313/2377; 631/80/313/2380; 82/58; 82/80; 82/83; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell surface; Cells, Cultured; Clathrin - metabolism; Cyclin-dependent kinase 5; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Dynamin; Dynamin I - genetics; Dynamin I - metabolism; Dynein; Elongation; Endocytosis; Endocytosis - genetics; Gene Expression Regulation; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Growth cones; Growth factors; HEK293 Cells; HeLa Cells; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Humanities and Social Sciences; Humans; Kinases; Mice; Mice, Inbred C57BL; Micronutrients; multidisciplinary; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neurons - metabolism; Protein Binding; Proteins; Receptor mechanisms; Receptors; Regulation; Regulators; RNA Interference; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22603-4

Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Fast Endophilin-mediated endocytosis, FEME, is not constitutively active but triggered upon receptor activation. High levels of growth factors induce spontaneous FEME, which can be suppressed upon serum starvation. This suggested a role for protein kinases in this growth factor receptor-mediated regulation. Using chemical and genetic inhibition, we find that Cdk5 and GSK3β are negative regulators of FEME. They antagonize the binding of Endophilin to Dynamin-1 and to CRMP4, a Plexin A1 adaptor. This control is required for proper axon elongation, branching and growth cone formation in hippocampal neurons. The kinases also block the recruitment of Dynein onto FEME carriers by Bin1. As GSK3β binds to Endophilin, it imposes a local regulation of FEME. Thus, Cdk5 and GSK3β are key regulators of FEME, licensing cells for rapid uptake by the pathway only when their activity is low. Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Here, the authors show that Cdk5 and GSK3β are negative regulators of fast Endophilin-mediated endocytosis (FEME).